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Tackling Treg mediated resistance to radiation and anti-PDL1 in HNSCCs

解决 HNSCC 中 Treg 介导的放射抗性和抗 PDL1

基本信息

批准号：
10590767
负责人：
SANA KARAM
金额：
$ 43.91万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10590767
关键词：
Adjuvant Radiotherapy Affect Animal Model Back Biological Assay Blood Blood specimen CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CXC chemokine receptor 3 CXCL9 gene CXCR3 gene Cell secretion Cells Chemotaxis Clinical Trials Design Coculture Techniques Cytometry Data FOXP3 gene Feeds Flow Cytometry Genetic Engineering Genetic Transcription Genetically Engineered Mouse Goals Growth Growth Factor Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Immune Immune Evasion Immune Targeting Immune checkpoint inhibitor Immunofluorescence Immunologic Immunotherapy In Vitro Infiltration Interferon Type II Investigational Therapies Knockout Mice Knowledge Laboratories LoxP-flanked allele Mediating Modeling Molecular Mus Neoadjuvant Therapy PD-L1 blockade Pathway interactions Patients Phase Phase I Clinical Trials Phenotype Phosphorylation Plasma Proliferating Radiation Radiation therapy Regulatory T-Lymphocyte Relapse Research Research Proposals Resistance Resistance development STAT1 gene STAT3 gene Signal Transduction Signaling Molecule T-Cell Activation T-Cell Depletion TCR Activation Testing Tissue Sample Tissues Up-Regulation anti-CTLA4 anti-PD-L1 anti-PD-L1 therapy anti-tumor immune response cancer cell carcinogenesis checkpoint therapy chemokine clinical trial analysis cofactor cytokine effective therapy effector T cell first-in-human genome sequencing high risk immune checkpoint blockade improved inhibitor inhibitor therapy knock-down migration mouse model negative affect novel therapeutic intervention pharmacologic phase I trial polarized cell potential biomarker programmed cell death ligand 1 recruit response synergism targeted treatment therapy development therapy resistant transcriptome sequencing tumor tumor eradication tumor microenvironment whole genome

项目摘要

Abstract Current treatment of head and neck squamous cell carcinoma (HNSCC) with immune checkpoint inhibitors and radiotherapy (RT) are initially effective, but relapse is common. The goal of our research is to understand mechanisms of response and resistance and to use this knowledge to improve therapy. We show that during the response phase to treatment, RT increases STAT1 phosphorylation, CXCL9/10 secretion, and PDL1 expression on cancer cells, and increases CD8 and CD4 infiltration and activation. These effects, however, dissipate in the resistance phase, and a significant increase in regulatory T cells (Tregs), STAT3, and TGF1 are observed. Treg depletion and anti-STAT3 targeting restores response to RT and anti-PDL1, resulting in suppression of plasma levels of TGF1, activation of T effector cells (Teff, Cd44+, IFN-G+ CD4 and CD8 T cells) and complete tumor eradication in an orthotopic model of HNSCC. This effect is unachievable with the addition of anti-CTLA4, anti-Tim3, or with hypofractionation of RT. Our in vitro preliminary data show that RT enhances STAT3 phosphorylation on CD4 T cells, leading to increased Treg conversion. This is reversed with STAT3 inhibitors. CD4 T cell conversion toward a Treg phenotype represents an important mechanism of immune evasion. TGF1 has been established as a necessary growth factor for conversion of naïve CD4 T cells to Tregs through induction of FoxP3 expression. In addition, STAT3 is a necessary transcription co-factor for FoxP3 expression. Our central hypothesis is that during the response phase, RT induces a distinct cancer cell STAT1-mediated CXCL9/10 secretion which recruits and activates Teff resulting in enhanced synergy with anti-PDL1. RT, however, also promotes CD4 conversion to Treg cells by phosphorylation of STAT3, which leads to the development of treatment resistance by inhibiting Teff function. Using knockdown constructs of STAT1 and CXCL9/10 on cancer cells and a CXCR3-/- mouse model, we will determine the effect of RT-induced chemokines in Teff chemotaxis, proliferation, and TCR activation (Aim1). To determine how RT affects CD4 T cell conversion and how that feeds back to negatively affect Teff function, we will use the CD4-Cre/ Stat3flox/flox mice with knockdown of STAT3 on CD4 T cells as well as STAT3 inhibitors (Aim2). Finally, we will use tissue and blood samples from a Phase I clinical trial aimed at using neoadjuvant combination RT and anti-PDL1 and will examine whether that changes the immune landscape to increase Teff/Treg ratio and enhance Teff activation profile (Aim3). We expect these studies to elucidate molecular and cellular parameters of RT plus immune checkpoint blockade and to help develop more effective therapy for HNSCC.

摘要